Ioannis Stefanidis

Disturbances of acquired immunity in hemodialysis patients

Acquired immunity disturbances in hemodialysis (HD) patients are many and diverse. They are caused by uremia per se, the HD procedure, chronic renal failure complications, and therapeutic interventions for their treatment. Current data suggest that acquired immunity disturbances in HD patients concern mainly the T‐lymphocyte and the antigen‐presenting cell (APC). The T‐lymphocyte‐dependent immune response is deficient, predisposing to infections and inadequate response to vaccinations. In addition, APCs are preactivated, which seems to be responsible for the malnutrition–inflammation–atherosclerosis syndrome, and also affects T‐lymphocyte function. At the molecular level it is assumed that the interaction between the APC and the T‐lymphocyte is impaired. This disturbance is likely to concern the signal that results from the interaction between the major histocompatibility complex:peptide complex on APC surfaces and T‐cell receptors on T‐lymphocyte surfaces, or the signal that results from the interaction among the co‐receptors of these two cells. The aim of the present review was to collect and classify the available clinical and experimental data in this area. Although many pieces are still missing from the puzzle, a better understanding of the responsible molecular mechanisms, will potentially lead to increased survival and a better quality of life in HD patients.

Basic Science and Dialysis: Disturbances of Acquired Immunity in Hemodialysis Patients

Acquired immunity disturbances in hemodialysis (HD) patients are many and diverse. They are caused by uremia per se, the HD procedure, chronic renal failure complications, and therapeutic interventions for their treatment. Current data suggest that acquired immunity disturbances in HD patients concern mainly the T‐lymphocyte and the antigen‐presenting cell (APC). The T‐lymphocyte‐dependent immune response is deficient, predisposing to infections and inadequate response to vaccinations. In addition, APCs are preactivated, which seems to be responsible for the malnutrition–inflammation–atherosclerosis syndrome, and also affects T‐lymphocyte function. At the molecular level it is assumed that the interaction between the APC and the T‐lymphocyte is impaired. This disturbance is likely to concern the signal that results from the interaction between the major histocompatibility complex:peptide complex on APC surfaces and T‐cell receptors on T‐lymphocyte surfaces, or the signal that results from the interaction among the co‐receptors of these two cells. The aim of the present review was to collect and classify the available clinical and experimental data in this area. Although many pieces are still missing from the puzzle, a better understanding of the responsible molecular mechanisms, will potentially lead to increased survival and a better quality of life in HD patients.

Endothelial NO Synthase Gene Polymorphisms and Hypertension: A Meta-Analysis

Studies investigated the association between endothelial NO synthase gene polymorphisms and hypertension-reported contradicted or nonconclusive results. A meta-analysis of 35 genetic association studies that examined the relation between hypertension and the G894T, 4a/b, T786C, and G23T polymorphisms of the endothelial nitric oxide synthase gene was carried out. Subgroup analysis by ethnicity and potential sources of heterogeneity and bias were explored. The meta-analysis included genotype data on 7779/10 498, 2216/3222, 2491/3913, and 833/587 cases/controls for G894T, 4b/a, T786C, and G23T, respectively. For the 4b/a polymorphism, overall, the heterogeneity between studies was not significant (P =0.82), and the allele b was associated with a 15% decreased risk of hypertension relative to allele a (odds ratio: 0.85; 95% CI: 0.74 to 0.98). Overall and in whites, the recessive model for allele b produced significant results (odds ratios: 0.78; 95% CI: 0.68 to 0.90 and OR: 0.76 95% CI: 0.62 to 0.92, respectively), whereas the dominant model produced nonsignificant results. In studies involved East Asians and blacks, an association was not demonstrated. Regarding the G894T, T768C, and G23T polymorphisms, in no case (ie, overall, in whites, or in East Asians) was a statistically significant association and heterogeneity found. There was no substantial source of bias in the selected studies. In conclusion, there is evidence of association only between 4b/a polymorphism and hypertension; however, studies exploring combinations of the polymorphisms may help us better understand the genetics of hypertension.

The relationship between C677T methylenetetrahydrofolate reductase gene polymorphism and retinopathy in type 2 diabetes : a meta-analysis

AbstractThe association between retinopathy in type 2 diabetes [diabetic retinopathy (DR)] and the C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene has been investigated in several case-control studies. These studies rendered contradictory results, some indicating that the polymorphism is associated with the risk of developing DR whereas others concluded there is no association. To shed light on these inconclusive findings, a meta-analysis of all available studies relating the C677T polymorphism to the risk of developing DR was conducted. Four out of five identified studies included populations of East Asian descent, and only one involved samples from European descent (Caucasians). Overall, the meta-analysis suggested large heterogeneity between studies (p = 0.08, I2 = 52%) and marginal association between C677T transition and the risk of developing DR: random effects odds ratio (OR) = 1.39 [95% CI (1.05, 1.83)]. The sensitivity analysis [exclusion of one East Asian study with the controls not in Hardy-Weinberg equilibrium (HWE)] showed no heterogeneity (p = 0.25, I2 = 27%) and no significant association: fixed effects OR = 1.22 [95% CI (0.99, 1.51)] and random effects OR = 1.24 [95% CI (0.96, 1.60)]. The sub-group analysis for the East Asian population produced a significant association: fixed effects OR = 1.48 [95% CI (1.20, 1.83)] and random effects OR = 1.52 [95% CI (1.14, 2.03)]. However, sensitivity analysis in East Asians revealed that the association is marginal: fixed effects OR = 1.33 [95% CI (1.04, 1.70)] and random effects OR = 1.36 [95% CI (1.01, 1.83)]. There is a source of bias in the selected studies: the largest studies failed to show association while the smallest study claimed an association. The above findings reinforce the need for larger and more rigourous studies in this area.

Low RLS prevalence and awareness in central Greece: an epidemiological survey

Restless legs syndrome (RLS) is a sensorimotor disorder with a general population prevalence of 3–10%. A single, previous epidemiological study performed in south‐east Europe reported the lowest prevalence rate amongst European countries. We conducted a population‐based survey of RLS in central Greece. A total of 4200 subjects were randomly recruited. We used the international RLS study group criteria for diagnosis and the severity scale for severity assessment in subjects with RLS. We also included questions to assess the level of awareness of RLS in our region. A total of 3033 subjects were screened. The overall lifetime prevalence was 3.9% with a female‐to‐male ratio of 2.6:1. Nearly half of RLS patients reported moderate to severe intensity of symptoms. After adjustment for multiple comparisons we found no association of RLS with education level, smoking, alcohol intake, caffeine consumption, shift work, professional pesticide use or comorbid illness. Our study revealed a low level of awareness amongst the population and physicians in our region and sub‐optimal management. We provide further evidence for low prevalence of RLS in south‐east Europe and a low level of awareness of RLS in our region.

Association between the GLUT1 gene polymorphism and the risk of diabetic nephropathy: a meta-analysis

AbstractThe association between diabetic nephropathy (DN) and the XbαI polymorphism in the GLUT1 gene has been investigated in several case-control studies. These studies rendered contradictory results: the allele XbαI(−) was shown either to be a risk factor or neutral, or even protective for the development of the disease. To shed some light on these inconclusive findings, a meta-analysis of all available studies relating the XbαI polymorphism to the risk of developing DN was conducted. Five out of six identified studies included Caucasian populations, and only one involved samples from an Asian population. Overall, the meta-analysis suggested large heterogeneity between studies (P<0.01, I2=68%) and lack of association between allele XbαI(−) and the risk of developing DN relative to allele XbαI(+): random effects odds ratio (OR)=1.26 [95% CI (0.93, 1.69)]. Excluding one study with the controls not in Hardy-Weinberg equilibrium, the sensitivity analysis revealed that heterogeneity (P=0.28, I2=21%) could be explained, and then, there is an overall association: fixed effects OR=1.34 [95% CI (1.13, 1.60)]. Then, significant ORs were also found on analysis of subgroups: for the Caucasian population, fixed effects OR=1.29 [95% CI (1.08, 1.56)] and for the type 2 diabetic patients fixed effects OR=1.69 [95% CI (1.09, 2.63)]. In type 1 diabetes, there is a moderate heterogeneity (P=0.19, I2=41%) with fixed effects OR=1.29 [95% CI (1.06, 1.56)] and random effects OR=1.32 [95% CI (1.01, 1.71)]. There is a source of bias in the selected studies: large studies failed to show association while small studies claimed an association. Although there is evidence of association between GLUT1 and DN, the above findings reinforce the need for further and more rigorous association studies.

Methylenetetrahydrofolate reductase gene polymorphism as a risk factor for diabetic nephropathy: a meta-analysis

AbstractInvestigations into the association between diabetic nephropathy (DN) and MTHFR C677T gene polymorphism in several case-control studies has yielded contradictory results. To shed light on these inconclusive findings, a meta-analysis of all available studies relating the C677T polymorphism to the risk of developing DN was conducted. The PubMed database was searched, and case-control studies investigating the association between MTHFR C677T gene polymorphism and DN were included in the meta-analysis. The meta-analysis included 15 studies, of which 8 involved Caucasians and 5 East Asians; 11 studies involved subjects with type 2 diabetes and 4 with type 1 diabetes. The main analysis (all studies) revealed significant heterogeneity between the studies (PQ < 0.01) and a marginal association between the 677T allele and the risk of developing DN; the random effects (RE) pooled odds ratio (OR) was 1.30 (1.03-1.64). However, the sensitivity analysis (exclusion of studies not in Hardy-Weinberg equilibrium) produced non-significant results. The recessive model derived significant results in main analysis [fixed effects (FE) OR = 1.32 (1.10-1.58), PQ = 0.27], and in type 2 diabetes [FE OR = 1.30 (1.06-1.60), PQ = 0.38]. The additive model produced significant association in main analysis [RE OR = 1.65 (1.13-2.42), PQ < 0.01] in Caucasians [FE OR = 1.48 (1.11-1.98), PQ = 0.17] and in type 2 diabetes [RE OR = 1.65 (1.03-2.67), PQ < 0.01]. However, sensitivity analysis diminished the significant results in type 2 diabetes. There is no differential magnitude of effect in large versus small studies. In conclusion, although there is some evidence of association between MTHFR C677T gene polymorphism and DN, the above findings reinforce the need for further and more rigorous association studies.

MEIS1 and BTBD9: genetic association with restless leg syndrome in end stage renal disease

Background Restless legs syndrome (RLS) is a sleep related movement disorder that occurs both in an idiopathic form and in symptomatic varieties. RLS is a frequent and distressing comorbidity in end stage renal disease (ESRD). For idiopathic RLS (iRLS), genetic risk factors have been identified, but their role in RLS in ESRD has not been investigated yet. Therefore, a case–control association study of these variants in ESRD patients was performed. Methods The study genotyped 10 iRLS associated variants at four loci encompassing the genes MEIS1, BTBD9, MAP2K5/SKOR1, and PTPRD, in two independent case–control samples from Germany and Greece using multiplex PCR and MALDI-TOF (matrix assisted laser desorption/ionisation time-of-flight) mass spectrometry. Statistical analysis was performed as logistic regression with age and gender as covariates. For the combined analysis a Cochran–Mantel–Haenszel test was applied. Results The study included 200 RLS-positive and 443 RLS-negative ESRD patients in the German sample, and 141 and 393 patients, respectively, in the Greek sample. In the German sample, variants in MEIS1 and BTBD9 were associated with RLS in ESRD (Pnom≤0.004, ORs 1.52 and 1.55), whereas, in the Greek sample, there was a trend for association to MAP2K5/SKOR1 and BTBD9 (Pnom≤0.08, ORs 1.41 and 1.33). In the combined analysis including all samples, BTBD9 was associated after correction for multiple testing (Pcorrected=0.0013, OR 1.47). Conclusions This is the first demonstration of a genetic influence on RLS in ESRD patients with BTBD9 being significantly associated. The extent of the genetic predisposition could vary between different subgroups of RLS in ESRD.

Renal manifestations and complications of inflammatory bowel disease

Renal manifestations and complications are not rare in patients with inflammatory bowel disease (IBD) and may present as nephrolithiasis, amyloidosis, tubulointerstitial nephritis, and glomerulonephritis. Symptoms of renal impairment are not always specific and since the underlying bowel disease is preponderant, renal function deterioration may be underestimated. Additionally, medical treatment of patients with IBD such as aminosalicylates, cyclosporine, and tumor necrosis factor‐&agr; inhibitors can cause renal complications, although direct correlation to bowel disease is not always clear. The well‐documented renal manifestations and complications of IBD, as well as the possible renal side effects of new drugs, emphasize the need for periodic evaluation of renal function. New markers of renal function may facilitate early diagnosis and unravel the complex mechanisms responsible for kidney damage. The purpose of this review is to summarize the renal manifestations and complications as well as the markers of renal function utilized in IBD, attempting to shed more light on the pathophysiology of renal damage in IBD. (Inflamm Bowel Dis 2011;)

The Role of Hepcidin in Iron Homeostasis and Anemia in Hemodialysis Patients

Anemia is a common complication in hemodialysis (HD) patients. Despite the great success of recombinant human erythropoietin in clinical practice, resistance to this therapy is common. Additionally, nephrologists frequently witness a rapid and significant drop in their patients’ hematocrit during the course of various acute events that regularly take place in this sensitive population. Hepcidin, a recently identified peptide, may mediate this development in many instances. Hepcidin production is regulated by hypoxia/anemia, iron status, and importantly, inflammation. This peptide can block iron absorption by the duodenum, iron release from both the liver (the main iron storage pool) and, more significantly, the macrophages interrupting iron recycling between senescent red cells and the reticuloendothelial system. The decreased availability of iron for erythropoiesis leads to the anemia of chronic disease or, in HD patients, aggravate an already existing anemia HD is now widely considered an inflammatory state probably accounting for the increased serum hepcidin levels that have been associated with it. The physiology of hepcidin and its possible contribution to the pathogenesis of anemia in HD patients are the subject of this review.